N-substituted anthranilic anhydrides

ABSTRACT

The compounds are N-carboxy-anthranilic anhydrides (isotoic annydride) used in the preparation of pharmacologically active tricyclic quinazolinones of the class of imidazo (2,1b)quinazolin-5-ones, pyrimido(2,1-b)quinazolin-6-ones and diazepino(2,1-b)quinazolin-7-ones, bearing an unsaturated substituent on the available nitrogen of the quinazolinone portion and useful, for example, as anti-inflammatory and bronchodilator agents.

United States Patent [191 Hardtmann 1 Oct. 14, 1975 [54] N-SUBSTITUTEDANT HRANILIC ANl-IYDRIDES [75] Inventor: Goetz E. Hardtmann, FlorhamPark,

[73] Assignee: Sandoz Inc., East Hanover, NJ.

[22] Filed: May 20, 1974 21 Appl. N0.I 471,317

Related U.S. Application Data [60] Division of Ser. No. 337,381, March2, 1973, Pat. No. 3,833,588, which is a continuation-in-part of Ser. No.247,435, April 25, 1972, abandoned.

[52] U.S. Cl. 260/244 A; 260/244 [51] Int. Cl. C07D 87/00 [58] Field ofSearch 260/244, 244 A [56] References Cited UNITED STATES PATENTS2,910,488 10/1959 Novello 260/244 R 3,351,659 11/1967 Satilli et al3,383,415 5/1968 Carabateas 260/244 R 3,729,473 4/1973 Boshagen et a1.260/244 R FOREIGN PATENTS OR APPLICATIONS 38-16891 3/1963 Japan 499,8226/1928 Germany Primary Examiner-Albert T. Meyers Assistant Examiner--D.W. Robinson Attorney, Agent, or FirmGerald D. Sharkin; Richard E. Vila[57] ABSTRACT 5 Claims, N0 Drawings N-SUBSTITUTED ANTHRANILIC ANHYDRIDESThe invention also relates to pharmaceutical methods and compositionsfor utilization of the compounds based on their biological activity} Thecompound 2,3-dihydro'l0-ethylimidazo[2,1- b]quinazolin-5(10H)-one, and amethodfor preparing it, are known from Doleschall et al., Acta Chim.Hung. 45, 357360[1965]. The article contains no indication whatsoever,however, that the compound possesses pharmacological activity. I havefound as disclosed in US. patent 3,598,823, that said compound and theclass of alkyl substituted compounds represented thereby possesspharmacological activity, in particular that they have bronchodilatoractivity.

The present invention provides pharmacologically active compounds of theformula I:

(CHILI wherein each of R and R is, independently, hydrogen, halo ofatomic weight not greater than 36 or lower alkyl of 1 to 3 carbon atoms,or are both lower alkoxy of 1 to 2 carbon atoms;.or one is hydrogen andthe other lower alkoxy .of.-1 to ,2 carbon atoms,

n is 0 to 2; and R is alkenyl of 3 to 10 carbon atoms, e.g. allyl,methallyl, crotyl, hexene-S and octene-7; alkynyl of 3 to 6 carbonatoms, e.g. propargyl; or cyanoalkyl of 2 too carbon atoms, and

each of R R R and R is hydrogen or alkyl of 1 to 3 carbon atoms providedno more than 3 of R R R and R are alkyl,

or a pharmaceutically acceptable acid addition salt thereof.

The generally preferred method for preparation of compounds of formula 1involves reacting in a Step A a compound of the formula 11:

wherein R R R R and n is as defined and Roh is lower alkyl or b'enzyl.

The preparation of compounds 1 by step A can be carried out attemperatures in the range of 20C. to

160C., more usually 20C. to 140C., preferably 80C.

to 120C; The reaction is conveniently carried out in an organic solventof conventional type providing an inert medium. The aromatic solventsand cyclic ethers suitable for use at reflux temperatures represent thepreferred solvents, e.g. toluene and dioxane. The reaction is preferablycarried out in the presence of a base, e.g. sodium hydroxide or sodiumcarbonate; and when the compound 111 is employed in acid addition saltform, it is of course desirably to employ an amount of base somewhatgreater than the amount necessary to neutralize the acid. The reactionproduct of formula I may be recovered from the reaction of Step A byworking up by conventional procedures.

The compounds of the formula III are known or may be prepared by knownprocedures while compounds 11 may be prepared from known material byestablished procedures involving reacting the corresponding -N-unsubstituted'isatoic anhydride with a strong base and the chloro or"bromo derivative of the R substituent at suitably 0C. to 80C. 1

Also within the scope of the invention are pharmaceuticallyacceptablesalts of the compounds 1. Such salts include the-acid addition salts ofknown type, e.g., the hydrochloride. The acid addition salts may beproduced from the free bases by conventional procedures. Conversely, thefree bases may be obtained from the salts by procedures known in theart.

The compounds of the formula I arev useful as antiinflammatory agents asindicated by an inhibition of Carrageenan induced edema in rats onoraladministration (15-50 mg./kg.). For such use, the compounds may becombined with a pharmaceutically acceptable carrier, and such otherconventional adjuvants as may be necessary, and administered orally insuch forms as tablets, capsules, elixirs, suspensions and the like orparenterally in the form of an injectable solution or suspension. Thedosage administered will, of course, vary depending upon the compoundused and the mode of administration. However, in general, satisfactoryresults are obtained when administered at a daily dosage offrom about1.5 milligrams toabout 150 milligrams per kilogram of body weight,preferably given in divided doses 2 to 4 times a day, or in sustainedrelease of the compound in admixture with a solid or liquidpharmaceutical carrier or diluent.

The compounds of the formula 1 are also useful as bronchodilator agentsas indicated by observing the respiratory status on oral administration(1.0 mgs./kgs.) to the unanesthetized guinea pig exposed to aerosolizedhistamine dihydrochloride according to a modification of the method ofVan Arman et al., J.

Pharm. Pharmacol. 17 374-385, I960; and in vitro by observing the effect(0.1 30 micrograms/ml.) on strips of guinea pig trachea according to themethod of Constantine, J. Pharm. Pharmacol. l7 384885, 1960. For suchuse and depending upn known variables satisfactory results are obtainedin general on the daily administration of from 0.5 to 100 milligrams perkilogram of body weight, preferably given in divided doses 2 to 4 timesa day, or in sustained release form. For most mammals the administrationof from 40 to 1500 milligrams per day provides satisfactory results anddosage forms suitable for internal administration comprise lO to 750milligrams of the compound in admixture with a solid or liquidpharmaceutical carrier or diluent.

For the above usages, the compounds may be combined with apharmaceutically acceptable carrier, and such other conventionaladjuvants as may be necessary, and administered orally or parenterally.For most uses oral administration with carriers is preferred and maytake place in such conventional forms as tablets, dis-' persiblepowders, granules, capsules, suspensions, syrups and elixirs. Suchcompositions may be prepared according to any method known in the artfor the manufacture of pharmaceutical compositions, and suchcompositions may contain one or more conventional adjuvants, such assweetening agents, flavoring agents, col- .oring agents and preservingagents, in order to provide an elegant and palatable preparation.Tablets may contain the active ingredient in admixture with conventionalpharmaceutical excipients, e.g., inert diluents such as calciumphosphate, calcium sulphate dihydrate, lactose and talc, granulating anddisintegrating agents,

- e.g., starch and alginic acid, binding agents, e.g., starch,

gelatin, polyvinylpyrrolidone and acacia, and lubricating agents, e.g.magnesium stearate, stearic acid and talc. The tablets may be uncoatedor coated by known techniques to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Similarly, suspensions, syrups an'delixirs may containthe active ingredient in admixture with any of the conventionialexcipients utilized for-the preparation of such compositions, e.g.,suspending agents (methylcellulose, tragacanth and sodium alginate),wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylenesorbitan monooleate) and preservative (ethyl-p-hydroxy-benzoate).Capsules may contain the active ingredient alone or admixed with aninert solid diluent, e.g., calcium carbonate, calcium phosphate andkaolin. The preferred pharmaceutical compositions from the standpoint ofpreparation and ease of administration are solid compositions,particularly hard-filled capsules and tablets. Parenteral administrationmay be in such conventional forms as injectionable solutions andsuspensions.

A representative formulation is a tablet for oral administration 2 to 4times a day for the treatment of inflammation or for prophylactictreatment of bronchial asthma and prepared by conventional tablettingtechniques to contain the following ingredients:

-Continued Ingredients r Weight ting.)

'l'ragacanth ll) Lactose l97.5 Corn Starch 25 'l'alcurn l5 MagnesiumStearate 2.5

' A representative formulation is also a capsule for oral administration2 to 4 times a day for the treatment of inflammation or for prophylactictreatment of bronchial asthma and prepared by conventional capsulatingtechniques to contain the following ingredients:

Capsule Ingredients Weight (mg) l0-(Z-butenyl)-2.3-dihydro-imidazo[2.l-b ]quinazolin-5( lOH )-one 50 Lactose 316 Sterotcx K (a triglyerolester lubricant) 2U intidazo[2.l-b]quinazolin-5( l0H)-onc 0.4 20% Ethylalcohol l0 4071 Ascorbic acid 1 I071 Freon l I I0 3071 Freon H4 l0 30%Freon I2 30 60% Buffer System 4 pH control qs.

Flavor q.s.

The following examples show representative compounds encompassed withinthe scope of this invention and the manner in which such compounds areprepared. However,'it is to be understood that the examples are forpurposes of illustration only.

EXAMPLE 1 erjrn STEP A: Preparation of N-allyl-isatoic anhydride To asolution of 30 g. of isatoic anhydride in 300 ml. of dimethylacetamideat room temperature is added, sodium hydride obtained by washing threetimes with pentane 9.0 g. of 57% suspension of sodium hydride in mineraloil. The resulting mixture is stirred for l hour at room temperature and24 g: of allyl bromide is added followed by stirring at room temperaturefor about 1 hour. The resulting mixture is concentrated in vacuo toabout one third itsvolurne, a mixture of ice and water added and theresulting precipitate filtered off, washed with water, dried underreduced pressure at 35C. The solid material is then dissolved inmethylene chloride, dried with sodium sulfate, treated with charcoal anddiethyl ether added to crystallize on evaporation in vacuoN-allyl-isatoic anhydride, m.p. lO2l04C.

STEP B: Preparation of l-allyl-2,3-dihydro-imidazo[2,1-b]quinazolin- H)-one.

A solution of g. of N-allyl-isatoic anhydride, 2.5 g. ofZ-methylmercapto-imidazoline and one pellet (about 100 mg.) sodiumhydroxide in 300 ml. of dioxane is refluxed with stirring for 3 hours.The resulting mixture is evaporated to dryness, the residue dissolved inmethylene chloride, and extracted twice with 2N hydrochloric acid. Thecombined aqueous extracts are washed with methylene chloride and thenwith diethyl ether and made basic with 2N sodium bicarbonate. Theresulting precipitate is filtered off, washed thoroughly with water,dried under reduced pressure, dissolved in methylene chloride, driedwith sodium sulfate, and the methylene chloride exchanged for diethylether to crystallize lO-allyl2,3-dihydro-imidazo[ 2, l -b]quinazolin-5(10H)-one, m.p. ll9l2lC.

EXAMPLE 2 The following compounds of the invention are preparedemploying the reaction which is exemplified in Example 1.

b]quinazolin-5( l0H)-one, m.p. 96-98C.

. lO-(4-pentenyl)-2,3-dihydro-imidazo[2,1- b]quinazolin-5(l0H)-one, m.p.ll27C.

l. 7-chloro-2,3-dihydrol 0-allyl-imidazo[ 2, l

b]quinazolin-5( 10H )-one.

.I. 10-( Z-methallyl )-2,3-dihydro-imidazo[ 2, l

b]quinazoline-5( l0H)-one, m.p. l43-l45C. K. 1 l-allyl-2,3,4,ll-tetrahydropyrimido[2,l-

b]quinazolin-5( lOH)-one, m.p. 73-75C.

l0-(7-octenyl)-2,3-dihydro-imidazo[2, lb]quinazolin-5( 10H )-one.

M. l0-(4-pentenyl )-7-chloro-2,3-dihydroimidazo[2, l-

b]quinazolin-5( lOH)-one, m.p. 7376C.

N. ll-(4-pentenyl)-2,3,4,l l-tetrahydropyrimido[2,l-

b]quinazolin-6-one, m.p. -98C.

O. l O-cyanomethyl-2,2-dimethyl-2,3-dihydroimidazo[2,l-b]quinazolin-5(l0H)-one.

P. 10-propargyl-2,2-dimethyl-2,3-dihydroimidazo[2,l-b]quinazolin-5(l0H)one, m.p. l27-l29C.

Q. lO-(4-pentenyl)-2-methyl-2,3-dihydro-imidazo[2,l-

b]quinazolin-5( l0H)-one, m.p. l04-l07C.

R. l l-(4-pentenyl)-3,3-dimethyl-2,3,4,ll-tetrahydropyrimido[2,l-b]quinazolin-6-one, m.p. 69-72C. What isclaimed is:

l. A compound of the formula:

wherein R is alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 6 carbonatoms or cyanoalkyl of 2 to 6 carbon atoms, and each of R and R isindependently hydrogen, fluoro, chloro or alkyl of l to 3 carbon atoms,or both are alkoxy of l or 2 carbon atoms; or one is hydrogen and theother alkoxy of l or 2 carbon atoms. 2. The compound of; claim 1 whereinR is alkenyl of 3 to 10 carbon atoms.

3. The compound of claim 1 wherein R is alkynyl of 3 to 6 carbon atoms.

4. The compound of claim 1 wherein R is cyanoalkyl of 2 to 6 carbonatoms.

5. The compound of claim 2 which is N-allyl-isatoic anhydride.

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1 wherein R isalkenyl of 3 to 10 carbon atoms.
 3. The compound of claim 1 wherein R isalkynyl of 3 to 6 carbon atoms.
 4. The compound of claim 1 wherein R iscyanoalkyl of 2 to 6 carbon atoms.
 5. The compound of claim 2 which isN-allyl-isatoic anhydride.